DESCRIPTION: (Applicant's Abstract): This is a competitive renewal to provide a major source of salary support for the applicant, Mary Jeanne Kreek, M.D., as a senior Research Scientist Awardee (and also as Principal Investigator and Scientific Director of an NIH-NIDA Treatment-Related Research Center). This award will allow the applicant to continue to spend a significant amount of time in science training and mentoring at the graduate, post-graduate level, science education at the undergraduate and high school level as well as science education of a more general public. The most effective treatments for the addictive diseases including opioid addiction, cocaine addiction, alcoholism and nicotine addiction, probably will be based on the fundamental understanding of the biological basis of addictive diseases; the physiological and pharmacological effects of drugs of abuse and of agents used for the treatment of drug addiction, and of the other medical and behavioral problems which frequently co-exist with specific addictions and may complicate treatment. Also, effective treatments and prevention may by facilitated by an understanding of the human molecular genetics underlying some cases of addictive diseases. Research activities will continue to identify and study the biological correlates of addictions, factors which affect treatment outcome and also, primarily, the molecular neurological basis of addiction. Specific projects include: Effects of Drugs of Abuse and Potential Therapeutic Agents on the Molecular Biology of Endogenous Opioids, Related Neuropeptides and their Receptors; Effects of Drugs of Abuse and Potential Therapeutic Agents on Opioid Receptor and Related Neurotransmitter Systems; Disposition; Biotransformation of Natural Synthetic Opioid Agonists, Antagonist and Related Peptides; Effects of Drugs of Abuse and Potential Therapeutic Agents on the Molecular Biology and Expression of the Stress Responsive Hypothalamic Pituitary Adrenal Axis; Effects of Cocaine on Endogenous Opioid - NMDA Complex Interactions; Neuroendocrine Effects of Addictive Drugs: Role of the Endogenous Opioids and Stress Responsivity in Addictive Diseases; Effects of Drugs of Abuse and Potential Therapeutic Agents on the Molecular Biology and Expression of the Stress Responsive Hypothalamic Pituitary Adrenal Axis; Effectiveness of LAAM in Managing Heroin Abusing Methadone Maintained Patients. Human gene polymorphism and molecular genetics of addictions and the opioid system; and continued prospective surveillance of the medical status of patients entering methadone maintenance treatment, determining the changing patterns of hepatitis B, hepatitis C, HIV-1 infection and codependence and the impact of treatment on their natural history.